Abstract CT159: A phase 2a evolutionarily informed, mathematically guided adaptive abiraterone trial in metastatic castrate resistant prostate cancer
Authors: Jingsong Zhang, Joel S. Brown, Jessica Cunningham, Evan Adler, Robert Gatenby
Journal: Cancer Research (2022)

Abstract Background: To achieve better prostate cancer control and to delay the emergency of treatment resistance, we developed an evolutionary game theory model using Lotka-Volterra equations with three competing prostate cancer "species": T+, Tp, and T-. T+ prostate cancer cells depend on exogenous androgen; Tp cells express CYP17A1, produce and depend on androgen; and T- cells are androgen-independent and abiraterone (abi)-resistant. We applied this model to guide the on and off treatment cycles with abi for metastatic castration resistant prostate cancer (mCRPC). At the first interim analysis with 11 patients, this approach was shown to prolong the time to cancer progression with less than 50% drug usage compared to the conventional continuous abi (Nat Commun. 2017). Here we present the updated data of this phase 2a study with a median follow up of 5.8 years. Methods: Men with asymptomatic or minimal symptomatic mCRPC were enrolled after they achieved &amp;gt; 50% PSA reduction with abi as a frontline therapy for mCRPC. The primary objective is feasibility and is measured by the percentage of abi responsive men who remain to be responsive to abi (defined as &amp;gt; 50% decline of the pre Abi PSA) after completing 2 adaptive treatment cycles. The secondary objective is to assess the clinical benefits by comparing the radiographic progression free survival (rPFS) and overall survival (OS) in men undergoing adaptive Abi therapy to a contemporaneous cohort of patients who met trial eligibility but received continuous abi dosing as standard of care (SOC). Computer simulations of each patient’s clinical course estimated critical evolutionary parameters and then tested alternative strategies for individuals in both cohorts. Result: 17 evaluable patients were enrolled at Moffitt Cancer Center between June 2015 and January 2019. 5 of the 17 patients have completed at least 5 adaptive therapy cycles and 4 remain on study treatment without imaging progression for &amp;gt; 52 months at the data cut off on 1/4/2022. The study is closed for enrollment after demonstrating the feasibility of adaptive therapy. 16 SOC patients treated with continuous abi for mCRPC between 2015 and 2018 were identified through retrospective chart reviewed. Clinical features like Gleason score and metastasis burden are similar between the two groups. Evolution-based application of abiraterone significantly improved (p&amp;lt;0.001) median rPFS (30.4 months) and median OS (58.5 months) in the adaptive group compared to the 14.3 months median rPFS and the 31.3 months median OS in the SOC group. Average cumulative dose in the adaptive cohort was 54% of SOC dosing. Conclusions: Adaptive Abi therapy is feasible in men who responded to Abi as a frontline therapy for mCRPC. The updated data with longer follow up demonstrated OS as well as rPFS benefits of our adaptive therapy approach with less drug usage compared to the conventional continuous Abi. Clinical trial information: NCT02415621 Citation Format: Jingsong Zhang, Joel S. Brown, Jessica Cunningham, Evan Adler, Robert Gatenby. A phase 2a evolutionarily informed, mathematically guided adaptive abiraterone trial in metastatic castrate resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT159.